T1DMS

The first (and currently only) in silico diabetes model accepted by the FDA as a substitute for pre-clinical animal testing of new treatment strategies for Type 1 Diabetes Mellitus.

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Overview

T1DMS is a computer simulator of the dynamics of the human metabolic glucose-insulin system. It is based on a kinetic model developed from quantitative knowledge of glucose-insulin metabolism in conjunction with data from a large-population human subject study.Click here to learn more …

In January 2008, T1DMS became the first computer tool accepted by the FDA as a substitute for animal trials in the pre-clinical testing of certain control strategies in Type 1 Diabetes Mellitus. Implemented in Simulink/MATLAB, T1DMS uses a well-defined set of interfaces for testing of closed loop, user-defined treatment scenarios.Click here to learn more …

Additionally, TEG distributes and supports a Distributed Version of the T1D metabolic simulator (with a smaller “sample” in silico patient population). This Distributed Version provides members of the wider diabetes research community with a T1DMS system for independent research and teaching.Click here to learn more …

The T1DMS Difference

Most diabetes models provide only average group-level responses to different treatment strategies based on study populations of randomized controlled clinical trials. Conversely, using T1DMS, pre-clinical testing and experiments are conducted at the level of an individual subject providing insight into the intra- and inter-personal differences seen in humans, in response to the treatment protocol.

The key advantages to using T1DMS are:

Individualized, intra-personal results

Inter-personal differences are revealed across the spectrum of human variation

T1DMS is, to our knowledge, the only model with pediatric and adolescent populations – others only have adults

Applications & Benefits

The capabilities of T1DMS have opened up new possibilities in the mission to bring novel treatments, protocols, and devices to diabetes patients. T1DMS gives researchers a well-defined and validated tool to assess diabetes treatment strategies and controls while saving time and money.

Specific R&D benefits include the following:

T1DMS has been shown to reduce the research, development and IDE approval process from 2.5 years to less than 1 year

T1DMS can save millions of dollars in bringing new devices and treatments to the marketplace, as an accepted replacement for pre-clinical animal studies

T1DMS enables rigorous device/protocol testing scenarios on virtual subjects that would not be possible/ethical in animal and human studies

T1DMS provides a variety of analysis tools and metrics to understand the simulation data. Such analyses include:

Blood glucose excursion analysis

Control Variability Grid Analysis

Error Grid – Continuous Glucose Analysis

Number of subjects experiencing low and high glucose episodes

Full range of individual (per subject) responses and population responses

The T1DMS system was developed through research efforts at the Universities of Padova and Virginia.

Specifically, using quantitative knowledge of human glucose-insulin metabolism, a kinetic simulation model thereof was created and refined. The parameters for this kinetic model were determined via triple tracer NMR and PET experiments using a large population of human subjects under a standardized meal protocol.

The T1DMS system employs these parameters to simulate glucose metabolism – and its regulation by insulin – during a meal at both the organ-tissue and whole-body levels (e.g., hepatic glucose production, muscle utilization, renal extraction).

Implemented in Simulink/MATLAB, T1DMS uses a well-defined set of interfaces for testing of closed loop, user-defined treatment scenarios in the Simulink controller block with prescribed meal profiles. Additionally, insulin pump injection parameters and accurate sensor noise profiles for several devices are incorporated into the simulator.

When combined with the FDA-accepted in silico human subject population, T1DMS comprises a well-defined, validated tool to assess results of a proposed closed loop system early in the development phase of treatment strategies and protocols. As such, it has been accepted by the FDA as a substitute for pre-clinical animal studies for various glucose control system scenarios.

The Epsilon Group provides simulation services to support examination of your proprietary algorithm, device, or compound under extensive and rigorous testing. Such simulations employ a large in silico subject population which spans the variability of persons with Type 1 Diabetes.

Simulation scenarios can be designed to model self-management/lifestyle patterns and/or clinical protocols. Additionally, scenarios which would be potentially dangerous and/or unethical in a clinical setting can be simulated to examine possible limitations of the device or intervention under study.

Specific simulation details include the following:

In Silico population

Two distinct sets of 300 in silico subjects

Set 1 is used for iterative testing

Set 2 is the “Gold Standard” set used in final simulation studies to be submitted to the FDA for IDE approval

*Several standard controller blocks are provided. Specific simulation scenarios may involve simple to complex closed-loop controls each of which may include manual insulin injections in addition to insulin dosing controlled by the specific simulation algorithm

In Silico Subject-Specific Data Available to Examine and Tune Treatment Options

Age

Body weight (kg)

‘Optimal’ subject-specific basal insulin dose rate (U/hr)

‘Optimal’ subject-specific carbohydrate ratio (CR, g/U)

‘Optimal’ subject-specific maximum drop (MD, mg/dl per Unit insulin)

Total daily insulin and a measure of insulin sensitivity (TDI, U/day)

Metabolic testing results may be simulated for individual subjects and incorporated into treatment plans prior to the regulated model run

Simulation Output (per Subject)*

Blood glucose (BG) values (mg/dl per minute)

Simulated sensor BG readings (mg/dl per minute)

Simulated time

Basal/Bolus insulin injections (pmol/minute)

CHO – carbohydrate meal dose and timing

Individual subject identification

Subject system states: optimal control vs. poor control with hypo/hyper-glycemia

*Additional model output may be collected per specific requirements of study

The UVA/Padova T1DMS distributed software is available from The Epsilon Group. It provides members of the wider diabetes research community with a T1DMS system for independent research and teaching. Furthermore, if your final goal is FDA IDE submission for a novel device, protocol, or treatment strategy, you can conduct early stage R&D using the distributed version of the software prior to initiating a final T1DMS simulation via TEG’s Simulation Services.

T1DMS is an integrated dynamic computer model of human insulin-glucose metabolism in the presence of Type 1 Diabetes. In the Distributed Version, each individual of an in silico population of 30 subjects responds to insulin dosing, dietary factors and exercise factors to simulate daily lifestyle or clinical testing of diabetes management strategies. The distributed version is identical in functionality to the full version. The study population is 30 subjects (10 adults, 10 adolescents and 10 children) – hence a smaller sample size for testing. They both require Matlab/Simulink and the curve-fitting toolbox. There are no differences in the functionality. The results of such simulations can be used to: (i) test the efficacy, safety, and limitations of new therapies under varying conditions, (ii) compare existing treatments, and (iii) bolster research and product development strategies.

*Several standard controller blocks are provided. Specific simulation scenarios may involve simple to complex closed-loop controls each of which may include manual insulin injections in addition to insulin dosing controlled by the specific simulation algorithm

In Silico Subject-Specific Data Available to Examine and Tune Treatment Options

Age

Body weight (kg)

‘Optimal’ subject-specific basal insulin dose rate (U/hr)

‘Optimal’ subject-specific carbohydrate ratio (CR, g/U)

‘Optimal’ subject-specific maximum drop (MD, mg/dl per Unit insulin)

Total daily insulin and a measure of insulin sensitivity (TDI, U/day)

Metabolic testing results may be simulated for individual subjects and incorporated into treatment plans prior to the regulated model run

Simulation Output (per Subject)*

Blood glucose (BG) values (mg/dl per minute)

Simulated sensor BG readings (mg/dl per minute)

Simulated time

Basal/Bolus insulin injections (pmol/minute)

CHO – carbohydrate meal dose and timing

Individual subject identification

Subject system states: optimal control vs. poor control with hypo/hyper-glycemia

*Additional model output may be collected per specific requirements of study

Insulin bolus is based on the blood glucose measurement and given 30 minutes prior to food intake

No exercise

Blood glucose targets define control

High Carbs / High Fat

High Carbs / Low Fat

Well-balanced meal

High Glycemic Index

Low Glycemic Index

Insulin stacking: an overestimation of the insulin bolus size occurs, causing an incorrect insulin:carbohydrate ratio (high); or, the subject has a high insulin sensitivity factor and gives themselves "a little more to cover dessert".

Insulin stacking and exercise: teenager eats an after-school snack, then administers incorrect bolus (high); shortly thereafter, teenager goes to sports practice with no temporary basal adjustment or suspension to compensate for exercise then participates in a long period of exercise.

Overestimates bolus and exercises strenuously for 1-2 hours after meal

Blood glucose targets define control

High Carbs / High Fat

High Carbs / Low Fat

Well-balanced meal

High Glycemic Index

Low Glycemic Index

Mis-timed insulin dosing: insulin given in anticipation of a meal, but, the meal is delayed; alternatively, the insulin bolus is given much after meal is consumed; not using combo bolus for high carbs / high fat meals.

Mismatch timing challenge - Risk of both Hypo-/Hyper- glycemia:

Do not ignore insulin on-board

Bolus too early (45 min or as specified) or bolus too late (45 min or as specified) relative to meal time

Blood glucose targets define control

High Carbs / High Fat

High Carbs / Low Fat

Well-balanced meal

High Glycemic Index

Low Glycemic Index

Hypoglycemia avoidance: insulin given appropriately for meals, but given at a consistently (slightly) lower dose than needed for blood glucose target range (or snack is not covered).

Hypoglycemia avoidance - Risk of Hyperglycemia:

Consistent meal/snack sizes and times

Do not ignore insulin on-board

Bolus 5 units under optimal insulin dose for all meals/snacks

Blood glucose targets define control

High Carbs / High Fat

High Carbs / Low Fat

Well-balanced meal

High Glycemic Index

Low Glycemic Index

Variable insulin sensitivity due to illness: insulin given appropriately for meals - based on measured blood glucose levels, but illness is present resulting in fever, vomiting, inability to eat.

Designed to meet the needs of both academic and commercial researchers, the DMMS for Research provides a powerful but easy-to-use platform for conducting simulations on Type 1, Type 2, and Pre-diabetic subjects.

Feature highlights:

Available for PC and Mac!

T1/T2/Pre-DM populations (larger, FDA-accepted T1 populations also available when TEG is employed to provide simulation services)